Use of peptidic bradykinin antagonists for the treatment and prevention of Alzheimer&#39;s disease

ABSTRACT

The invention relates to the use of bradykinin antagonists for the production of pharmaceuticals for the treatment and prevention of Alzheimer&#39;s disease. Suitable bradykinin antagonists are peptides which inhibit the effects of the Alzheimer&#39;s protein amyloid (β/A4) on isolated endothelial cells. A particularly suitable peptide is H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140) and its physiologically tolerable salts.

The present invention relates to the use of bradykinin antagonists forthe treatment and/or prevention of Alzheimer's disease.

Bradykinin and related peptides are potent vasoactive, endogenoussubstances causing inflammation and pain. The use of bradykininantagonists as agents for the control of conditions which are mediated,triggered and supported by bradykinin has been disclosed in EP-A-0 370453, which is specifically incorporated by reference herein.

The importance of localized inflammation for the destructive changes inthe brains of patients with Alzheimer's disease is increasinglyrecognized. Inflammatory changes lead to chronicity and to continuingdestruction of the brain, and thus to severe dementia (J. Rogers,Inflammation as a pathogenic mechanism in Alzheimer's disease,Arzneimittelforschung 1995; 45 (3A),439-442). It was previously unknownthat bradykinin, a strongly inflammatory mediator in the periphery,could play a part in Alzheimer's disease. This is to be attributed tothe fact that there was no evidence of the release of bradykinin in thebrains of patients with Alzheimer's disease. The inactive high molecularweight precursors from which bradykinin is released cannot pass directlyinto the brain (neuronal tissue), namely because of the low permeabilityof the blood-brain barrier.

Other investigations have shown that the Alzheimer's protein β/A4 canstimulate the release bradykinin from the endothelium of vascular walls.The essential pathological changes of Alzheimer's disease are ascribedto the Alzheimer proteinβ/A4. See, for example, C. L. Joachim and D. J.Selkoe, The seminal role of beta-amyloid in the pathogenesis ofAlzheimer disease, Alzheimer Dis. Assoc. Disord., 1992 Spring, vol.6(1), pp. 7-34. If the release of the inflammatory bradykinin is shownto be due to a mechanism which is specific for Alzheimer's disease,bradykinin will become a pathophysiological factor of first rank, viawhich the Alzheimer's protein can mediate its destructive action. Thisapplies especially to inflammation, whose importance for the destructivechanges is increasingly recognized, since bradykinin is one of the mostpotent endogenous inflammatory substances.

Beside the inflammatory action, bradykinin additionally has two otherproperties through which it can contribute to the destructive changes inAlzheimer's disease. Bradykinin stimulates CNS neurons. In the case ofsevere stimulation, this leads to calcium overloading of the affectedcells, with subsequent cell death. On moderate stimulation, bradykininonly becomes a false transmitter, which inadequately stimulates neurons.Such an inadequate stimulation of neurons, which actually should not bestimulated at all, can sensitively interfere with the process ofinformation processing in the brain and contribute to the typical brainpower disorders, the latter mechanism, induced by moderate stimulation,appearing to be reversible.

As a vasoactive mediator, bradykinin increases, as is known, thepermeability of the blood-brain barrier. This leads to the fact that theprecursors of bradykinin can first pass from the blood vessels into thebrain, in order to display their destructive action there.

Surprisingly, it has now been found that bradykinin antagonists aresuitable agents for the treatment and prevention of Alzheimer's disease.This relates both to the intention to prevent progress of the diseaseand to treat symptoms which have already appeared. Moreover, bradykininantagonists can also be used preventively in order to prevent theorigination of Alzheimer's disease if in the future it should becomepossible by means of suitable diagnostic measures to predict a lateroutbreak of the disease.

Suitable compounds are bradykinin antagonists which inhibit the effectsof the Alzheimer's protein amyloid (β/A4) on isolated endothelial cells.

Preferred bradykinin antagonists are, inter alia, the peptides of theformula (I):

Z—P—A—B—C—E—F—K—(D)Q—G—M—F′—I  (I)

in which

Z is

a₁) hydrogen, (C₁-C₈)-alkyl, (C₁-C₈)-alkanoyl, (C₁-C₈)-alkoxycarbonyl,(C₃-C₈)-cycloalkyl, (C₄-C₉)-cycloalkanoyl, or (C₁-C₈)-alkylsulfonyl,

(1) in which 1, 2 or 3 hydrogen atoms in each of (C₁-C₈)-alkyl,(C₁-C₈)-alkanoyl, (C₁-C₈)-alkoxycarbonyl, (C₃-C₈)-cycloalkyl,(C₄-C₉)-cycloalkanoyl or (C₁-C₈)-alkylsulfonyl are optionally replacedby 1, 2 or 3 identical or different radicals selected from carboxyl,(C₁-C₄)-alkyl, (C₁-C₈)-alkylamino, (C₆-C₁₀)-aryl-(C₁-C₄)-alkylamino,hydroxyl, (C₁-C₄)-alkoxy, halogen, Di-(C₁-C₈)-alkylamino,Di-{(C₆-C₁₀)-aryl-(C₁-C₄)}-alkylamino, carbamoyl, phthalimido,1,8-naphthalimido, sulfamoyl, (C₁-C₄)-alkoxycarbonyl, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₅)-alkyl, NHR(1), {(C₁-C₄)-alkyl}NR(1) or{(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl}NR(1), where R(1) is hydrogen or a urethaneprotective group, or

(2) 1 or 2 hydrogen atoms in each of (C₁-C₈)-alkyl, (C₁-C₈)-alkanoyl,(C₁-C₈)-alkoxycarbonyl, (C₃-C₈)-cycloalkyl, (C₄-C₉)-cycloalkanoyl or(C₁-C₈)-alkylsulfonyl are replaced by 1 or 2 identical or differentradicals selected from carboxyl, amino, (C₁-C₈)-alkylamino, hydroxyl,(C₁-C₄)-alkoxy, halogen, di-(C₁-C₈)-alkylamino, carbamoyl, sulfamoyl,(C₁-C₄)-alkoxycarbonyl, (C₆-C₁₄)-aryl and (C₆-C₁₄)-aryl-(C₁-C₅)-alkyl,and 1 hydrogen atom in each of (C₁-C₈)-alkyl, (C₁-C₈)-alkanoyl,(C₁-C₈)-alkoxycarbonyl, (C₃-C₈)-cycloalkyl, (C₄-C₉)-cycloalkanoyl, or(C₁-C₈)-alkylsulfonyl is optionally replaced by a radical selected from(C₃-C₈)-cycloalkyl, (C₁-C₆)-alkylsulfonyl, (C₁-C₆)-alkylsulfinyl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkylsulfonyl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkylsulfinyl, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryloxy,(C₃-C₁₃)-heteroaryl and (C₃-C₁₃)-heteroaryloxy,

a₂) (C₆-C₁₄)-aryl, (C₇-C₁₅)-aroyl, (C₆-C₁₄)-arylsulfonyl,(C₃-C₁₃)-heteroaryl, or (C₃-C₁₃)-heteroaroyl, or

a₃) carbamoyl which can optionally be substituted on the nitrogen by(C₁-C₈)-alkyl, (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₅)-alkyl, where forthe radicals defined under a₁), a₂) and a₃) the aryl, heteroaryl, aroyl,arylsulfonyl and heteroaroyl groups are optionally substituted by 1, 2,3 or 4 radicals selected from carboxyl, amino, nitro,(C₁-C₈)-alkylamino, hydroxyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl, (C₇-C₁₅)-aroyl, halogen, cyano, di-(C₁-C₈)-alkylamino,carbamoyl, sulfamoyl and (C₁-C₆)-alkoxycarbonyl;

P is a direct bond or a radical of the formula (II),

—NR(2)—(U)—CO—  (II)

in which

R(2) is hydrogen, methyl or a urethane protective group,

U is (C₃-C₈)-cycloalkylidene, (C₆-C₁₄)-arylidene, (C₃-C₁₃)-heteroarylidene, (C₆-C₁₄)-aryl-(C₁-C₆)-alkylidene, each of which canoptionally be substituted, or is {CHR(3)}_(n), where n is 1-8,preferably 1-6, and

R(3) independently of one another is hydrogen, (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₄)-aryl or (C₃-C₁₃)-heteroaryl, which with theexception of the hydrogen are in each case optionally monosubstituted byamino, substituted amino, amidino, substituted amidino, hydroxyl,carboxyl, carbamoyl, guanidino, substituted guanidino, ureido,substituted ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl,4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl,phthalimido, 1,8-naphthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl,

where the substituted amino preferably is —N(A′)—Z, the substitutedamidino preferably is —(NH)C—NH—Z, the substituted guanidino preferablyis —N(A′)—C(N(A′))—NH—Z and the substituted ureido preferably is—C(O)—N(A′)—Z, in which A′ independently of one another is Z, Z beingdefined as under a₁) or a₂),

or in which

U is {CHR(3)}_(n), where n is 1-8, preferably 1-6, and R(2) and R(3)together with the atoms carrying these radicals form a mono-, bi- ortricyclic ring system having 2 to 15 carbon atoms;

A is defined as P;

B is a basic amino acid in the L or D configuration, which can besubstituted in the side chain;

C is a compound of the formula (IIIa) or (IIIb)

G′—G′—Gly  (IIIa)

G′—NH—(CH₂)_(p)—CO  (IIIb)

in which

p is 2 to 8, and

G′ independently of one another is a radical of the formula (IV)

—NR(4)—CHR(5)—CO—  (IV)

in which

R(4) and R(5) together with the atoms carrying these radicals form aheterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbonatoms;

E is the radical of a neutral, acidic or basic, aliphatic oralicyclic-aliphatic amino acid;

F is the radical of a neutral, acidic or basic, aliphatic or aromaticamino acid which can be substituted in the side chain, or a direct bond;

K is the radical —NH—(CH₂)_(x)—CO— where x=1-4 or a direct bond;

(D)Q is D-Tic, D-Phe, D-Oic, D-Thi or D-Nal, each of which canoptionally be substituted by halogen, methyl or methoxy, or a radical ofthe formula (V) below

in which

X is oxygen, sulfur or a direct bond, and

R is hydrogen, (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₄)-aryl or(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl,

where the alicycle of formula (V) can optionally be substituted byhalogen, methyl or methoxy;

G is defined as G′ above or is a direct bond;

M is defined as F;

F′ is defined as F, is a radical —NH—(CH₂)_(q)—, where q=2 to 8, or, ifG is not a direct bond, is a direct bond; and

I is —OH, —NH₂ or NHC₂H₅, wherein I is not directly bonded to D(Q);

or a physiologically tolerable salt thereof.

Suitable bradykinin antagonists and their preparation are described, forexample, in the Patent Applications WO 95/07294 (Scios Nova,Pseudopeptides), WO 94/08607 (Scios Nova, Pseudopeptides), WO 94/06453(Stewart, aliphatic amino acid in 5-position), WO 93/11789 (Nova), EP-A552 106 (Adir), EP-A 578 521 (Adir), WO 94/19372 (Scios Nova,Cyclopeptides), EP-A 370 453 (Hoechst), EP-A 472 220 (Syntex), WO92/18155 (Nova), WO 92/18156 (Nova), WO 92/17201 (Cortech) and WO94/11021 (Cortech; bradykinin antagonists of the formula X(BKA)_(n), inwhich X is a connecting link, BKA is the peptide chain of a bradykininantagonist and n is an integer greater than 1; bradykinin antagonists ofthe formula X(BKA); and bradykinin antagonists of the formula(Y)(X)(BKA) where Y is a ligand which is an antagonist or an agonist fora nonbradykinin receptor), the disclosures of all of which arespecifically incorporated by reference herein.

Particularly suitable peptides of the formula (I) are those in which:

Z is as defined above under a₁), a₂) or a₃);

P is a bond or a radical of the formula (II)

—NR(2)—(U)—CO—  (II)

where

U is CHR(3),

R(3) is as defined above, and

R(2) is H or CH₃, wherein R(2) and R(3) together with the atoms carryingthese radicals can form a mono-, bi- or tricyclic ring system having 2to 15 carbon atoms; and

A is a direct bond.

In particular, preferred compounds of the formula (I) are those inwhich:

Z is as defined above under a₁), a₂) or a₃);

P is a bond or a radical of the formula (II)

—NR(2)—(U)—CO—  (II)

where

R(2) is H or CH₃,

U is CHR(3) and

R(3) independently of one another is hydrogen, (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₄)-aryl, (C₃-C₁₃)-heteroaryl, which with theexception of the hydrogen in each case are optionally monosubstituted byamino, substituted amino, hydroxyl, carboxyl, carbamoyl, guanidino,substituted guanidino, ureido, mercapto, methylmercapto, phenyl,4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl,4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl,

where substituted amino preferably is —N(A′)—Z and substituted guanidinopreferably is —N(A′)—C(N(A′))—NH—Z, in which A′ independently of oneanother is Z, where Z is as defined under a₁) or a₂), or

in which R(2) and R(3) together with the atoms carrying these radicalsform a mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms;

A is a bond; and

(D)Q is D-Tic.

The following are preferably suitable:

H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140);

para-guanidobenzoyl-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-HypE(transpropyl)-Oic-Arg-OH;

H-D-Arg-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Cpg-Cpg-Arg-OH;

H-D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

H-Arg(Tos)-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH;

H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH;

Fmoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

Fmoc-Aoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-O H;

Fmoc-ε-aminocaproyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

benzoyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

cyclohexylcarbonyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

Fmoc-Aeg(Fmoc)-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

Fmoc-Aeg(Fmoc)-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

indol-3-yl-acetyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

dibenzylacetyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

and their physiologically tolerable salts.

The following are particularly suitable:

H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140);

para-guanidobenzoyl-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;

and their physiologically tolerable salts.

H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140) and itsphysiologically tolerable salts are very particularly suitable.

Preferred salts are alkali metal or alkaline earth metal salts, saltswith physiologically tolerable amines and salts with inorganic ororganic acids such as, for example, HCl, HBr, H₂SO₄, H₂PO₄, maleic acid,fumaric acid, citric acid, tartaric acid and acetic acid.

Administration can be carried out enterally, parenterally, such as, forexample, subcutaneously, i.m. or i.v., nasally, rectally or byinhalation. The dose of the active compound depends on the body weight,age and on the manner of administration.

The pharmaceutical preparations of the present invention are prepared indissolving, mixing, granulating, tabletting or sugar-coating processesknown per se.

For parenteral administration, the active compounds or theirphysiologically tolerable salts are brought into solution, suspension oremulsion, if desired using the pharmaceutically customary auxiliaries,for example for isotonicization or pH adjustment, and solubilizers,emulsifiers or other auxiliaries.

For the pharmaceuticals described, the use of injectable delayed releasepreparations for subcutaneous or intramuscular administration is alsoefficient. The pharmaceutical forms used can be, for example, oilycrystal suspensions, microcapsules, microparticles, nanoparticles orimplants, the latter being constructed from tissue-compatible polymers,in particular biodegradable polymers, such as, for example, on the basisof polylactic acid/polyglycolic acid copolymers. Other conceivablepolymers are polyamides, polyesters, polyacetates or polysaccharides.

For the oral administration form, the active compounds are mixed withthe additives customary for this purpose such as excipients, stabilizersor inert diluents and are brought by customary methods into suitableadministration forms, such as tablets, coated tablets, dry-filledcapsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholicor oily solutions. Inert excipients which can be used are, for example,gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate,lactose, glucose, magnesium stearyl fumarate or starch, in particularcorn starch. The preparation of solid pharmaceutical forms in this casecan take place both as dry and moist granules. Suitable oily excipientsor solvents are, for example, vegetable or animal oils, such assunflower oil and cod liver oil.

Oral delayed release preparations or preparations having entericcoatings are also conceivable. Delayed release preparations can beconstructed on the basis of fat, wax or polymer embeddings. Multilayeror press-coated tablets or pellets are also possible here.

For the pharmaceuticals described, administration to mucous membranes toachieve systemically active levels is also efficient. This relates tothe possibility of use intranasally, by inhalation and rectally.

For the intranasal administration form, the compounds are mixed with theadditives customary for this purpose such as stabilizers or inertdiluents and are brought by customary methods into suitableadministration forms, such as powder, aqueous, alcoholic or oilysuspensions or aqueous, alcoholic or oily solutions. Chelating agents,such as ethylenediamine-N,N,N′,N′-tetraacetic acid and buffers such asacetic acid, phosphoric acid, citric acid, tartaric acid and their saltscan be added to aqueous intranasal preparations. Multidose containerscontain preservatives such as benzalkonium chloride, chlorobutanol,chlorhexidine, sorbic acid, benzoic acid, PHB estes or organomercurycompounds.

The administration of the nasal solutions can take place by means ofmetered atomizers or as nasal drops with a viscosity-enhancing componentor nasal gels or nasal creams.

For administration by inhalation, atomizers or pressurized gas packsusing inert carrier gases can be used.

For the administration of powders for nasal or pulmonary inhalation,special applicators are necessary.

The efficacious dose is at least 0.001 mg/kg/day, preferably at least0.01 mg/kg/day, at most 5 mg/kg/day, preferably 0.03 to 1 mg/kg/day ofbody weight, depending on the degree of severity of the symptoms, basedon an adult of body weight 75 kg.

The abbreviations used for amino acids correspond to the three lettercode customary in peptide chemistry, as is described in Europ. J.Biochem 138,9 (1984). Other abbreviations used are listed below:

Aeg N-(2-aminoethyl)glycine

Cpg cyclopentylglycyl

Fmoc 9-fluoroenylmethoxycarbonyl

Nal 2-naphthylalanyl

Oic cis,endo-octahydroindole-2-carbonyl

Thi 2-thienylalanyl

Tic 1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl

EXAMPLE 1

Action of the compounds of the formula (I) on cGMP production stimulatedby the Alzheimer protein β/A4 in endothelial cell cultures

Test Systems

Bovine aortic endothelial cell cultures (BAECs=bovine aortic endothelialcells), intravascular coronary rat endothelial cell cultures (RMCECs=ratmicrovascular coronary endothelial cells) and human umbilical veinendothelial cell cultures (HUVECs=human umbilical vein endothelialcells)

Method

Determination of the effect of bradykinin antagonists of the formula (I)on the production of cGMP stimulated by administration of 0.1 and 1μmol/l of the Alzheimer protein β/A4 in endothelial cell cultures ofvarious species and organs.

cGMP

cyclic guanosine monophosphate

It has been adequately shown that endothelial cells are a suitable testsystem for the demonstration of an action and release of bradykinin (G.Wiemer et al., Hypertension 1991; 18:558-563). In endothelial cells,bradykinin leads to an increase in the production of cGMP, which isdetermined by means of a radioimmunoassay. Increase in the formation ofcGMP by bradykinin is an indicator of a release of NO (nitrogenmonoxide) from endothelial cells.

Experiment

Stimulation of cGMP production by βA(1-40) and inhibitory effect of thebradykinin antagonist HOE 140 (10⁻⁷ mol/l) in 3 different types ofendothelial cells:

pmol/mg of protein Endothelial cell type BAECs RMCECs HUVECs Basal cGMPproduction 2.2 ± 0.35  0.2 ± 0.07 4.75 ± 0.4 BK 10^(−8 mol/l) 8.8 ± 0.341.13 ± 0.2  11.46 ± 2   BK 10^(−8 mol/l + HOE 140) 2.2 ± 0.2  0.22 ±0.02  3.45 ± 0.45 βA (1-40) 10⁻⁷ mol/l 5.9 ± 0.23 0.59 ± 0.07 14.07 ±1.6  βA (1-40) 10⁻⁷ mol/l + HOE 2.2 ± 0.28 0.34 ± 0.02  4.0 ± 0.46 140βA (1-40) 10⁻⁶ mol/l 4.6 ± 0.13 0.74 ± 0.09 15.3 ± 1.9 βA (1-40) 10⁻⁶mol/l + HOE 2.2 ± 0.2  0.32 ± 0.05  5.3 ± 0.49 140

Results

The simultaneous incubation of the above mentioned cell cultures ofdifferent species and organs with HOE 140 as a representative example ofthe compounds of the formula (I) in a concentration of 0.1 μmol/lprevents the stimulation of the production of cGMP induced by the β/A4protein.

Assessment

The experiment carried out indicates that the action of the Alzheimerprotein β/A4 on the production of cGMP is mediated by a binding ofbradykinin to its cell receptors. Endothelial cell cultures serve hereas an indicator that the action of β/A4 is mediated by bradykinin. Theendothelial cells here are, however, not only the indicator system foran action on bradykinin receptors, but also the effector organ inAlzheimer's disease. Endothelial cells are constituents of the bloodvessels and line the latter. The blood vessels themselves are severelyaffected by deposits of the Alzheimer protein amyloid (β/A4) inAlzheimer's disease in addition to neuronal tissue. Endothelial cellsare responsible for an increase in the permeability of the blood-brainbarrier induced by bradykinin.

17 10 amino acids amino acid single linear unknown /note= “1= Xaa isD-Arg; 4= Xaa is 4Hyp; 6= Xaa is 2-thienylalanyl; 8= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 9= Xaa iscis,endo-octahydroindole-2-carbonyl” 1 Xaa Arg Pro Xaa Gly Xaa Ser XaaXaa Arg 1 5 10 9 amino acids amino acid single linear unknown /note= “1=Xaa is para-guanidobenzoyl- Arg; 3= Xaa is 4Hyp; 5= Xaa is2-thienylalanyl; 7= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl;8= Xaa is cis,endo-octahydroindole-2-carbonyl” 2 Xaa Pro Xaa Gly Xaa SerXaa Xaa Arg 1 5 10 amino acids amino acid single linear unknown /note=“1= Xaa is D-Arg; 4= Xaa is 4Hyp; 8= Xaa is D-HypE(transpropyl); 9= Xaais cis,endo-octahydroindole-2-carbonyl” 3 Xaa Arg Pro Xaa Gly Phe SerXaa Xaa Arg 1 5 10 10 amino acids amino acid single linear unknown/note= “1= Xaa is D-Arg; 4= Xaa is 4Hyp; 6= Xaa is cyclopentylglycyl; 8=Xaa is D-cyclopentylglycyl; 9= Xaa is cyclopentylglycyl” 4 Xaa Arg ProXaa Gly Xaa Ser Xaa Xaa Arg 1 5 10 10 amino acids amino acid singlelinear unknown /note= “1= Xaa is D-Arg; 6= Xaa is 2-thienylalanyl; 8=Xaa is D-1,2,3,4- tetrahydroisoquinolin-3-ylcarbonyl; 9= Xaa iscis,endo-octahydroindole-2-carbonyl” 5 Xaa Arg Pro Pro Gly Xaa Ser XaaXaa Arg 1 5 10 9 amino acids amino acid single linear unknown /note= “1=Xaa is Arg(Tos); 3= Xaa is 4Hyp; 5= Xaa is 2-thienylalanyl; 7= Xaa isD-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 8= Xaa iscis,endo-octahydroindole-2-carbonyl” 6 Xaa Pro Xaa Gly Xaa Ser Xaa XaaArg 1 5 9 amino acids amino acid single linear unknown /note= “1= Xaa isArg(Tos); 3= Xaa is 4Hyp; 7= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 8= Xaa is cis,endo-octahydroindole- 2-carbonyl” 7 Xaa ProXaa Gly Phe Ser Xaa Xaa Arg 1 5 10 amino acids amino acid single linearunknown /note= “1= Xaa is D-Arg; 4= Xaa is 4Hyp; 8= Xaa isD-1,2,3,4-tetrahydroisoquinolin- 3-ylcarbonyl; 9= Xaa iscis,endo-octahydroindole- 2-carbonyl” 8 Xaa Arg Pro Xaa Gly Phe Ser XaaXaa Arg 1 5 10 10 amino acids amino acid single linear unknown /note=“1= Xaa is 9-fluoroenylmethoxycarbonyl-D-Arg; 4= Xaa is 4Hyp; 6= Xaa is2-thienylalanyl; 8= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 9= Xaa iscis,endo-octahydroindole-2-carbonyl” 9 Xaa Arg Pro Xaa Gly Xaa Ser XaaXaa Arg 1 5 10 11 amino acids amino acid single linear unknown /note=“1= Xaa is 9-fluoroenylmethoxycarbonyl-cis,endo-2-azabicyclo[3.3.0]octane-3-S-canbonyl; 2= Xaa is D-Arg; 5= Xaa is 4Hyp; 7= Xaa is2-thienylalanyl; 9= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 10= Xaa is cis,endo-octahydroindole-2-carbonyl” 10 Xaa XaaArg Pro Xaa Gly Xaa Ser Xaa Xaa Arg 1 5 10 11 amino acids amino acidsingle linear unknown /note= “1= Xaa is9-fluoroenylmethoxycarbonyl-e-aminocaproyl; 2= Xaa is D-Arg; 5= Xaa is4Hyp; 7= Xaa is 2-thienylalanyl; 9= Xaa isD-1,2,3,4-tetrahydroisoquinolin- 3-ylcarbonyl; 10= Xaa iscis,endo-octahydroindole-2-carbonyl” 11 Xaa Xaa Arg Pro Xaa Gly Xaa SerXaa Xaa Arg 1 5 10 10 amino acids amino acid single linear unknown/note= “1= Xaa is Benzoyl-D-Arg; 4= Xaa is 4Hyp; 6= Xaa is2-thienylalanyl; 8= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl;9= Xaa is cis,endo-octahydroindole-2-carbonyl” 12 Xaa Arg Pro Xaa GlyXaa Ser Xaa Xaa Arg 1 5 10 10 amino acids amino acid single linearunknown /note= “1= Xaa is Cyclohexylcarbonyl- D-Arg; 4= Xaa is 4Hyp; 6=Xaa is 2-thienylalanyl; 8= Xaa isD-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 9= Xaa iscis,endo-octahydroindole-2-carbonyl” 13 Xaa Arg Pro Xaa Gly Xaa Ser XaaXaa Arg 1 5 10 11 amino acids amino acid single linear unknown /note=“1= Xaa is 9-fluoroenylmethoxycarbonyl-N-(2-aminoethyl)glycyl(9-fluoroenylmethoxycarbonyl; 2= Xaa is D-Arg; 5= Xaa is 4Hyp; 7= Xaa is2-thienylalanyl; 9= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 10= Xaa is cis,endo- octahydroindole-2-carbonyl” 14 XaaXaa Arg Pro Xaa Gly Xaa Ser Xaa Xaa Arg 1 5 10 10 amino acids amino acidsingle linear unknown /note= “1= Xaa is9-fluoroenylmethoxycarbonyl-N-(2-aminoethyl)glycyl(9-fluoroenylmethoxycarbonyl; 4= Xaa is 4Hyp; 6= Xaa is 2-thienylalanyl;8= Xaa is D-1,2,3,4- tetrahydroisoquinolin-3-ylcarbonyl; 9= Xaa iscis,endo-octahydroindole-2-carbonyl” 15 Xaa Arg Pro Xaa Gly Xaa Ser XaaXaa Arg 1 5 10 10 amino acids amino acid single linear unknown /note=“1= Xaa is Indol-3-yl-acetyl- D-Arg; 4= Xaa is 4Hyp;6= Xaa is2-thienylalanyl; 8= Xaa is D-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl;9= Xaa is cis,endo-octahydroindole-2-carbonyl” 16 Xaa Arg Pro Xaa GlyXaa Ser Xaa Xaa Arg 1 5 10 10 amino acids amino acid single linearunknown /note= “1= Xaa is Dibenzylacetyl-D-Arg ; 4= Xaa is 4Hyp; 6= Xaais 2-thienylalanyl; 8= Xaa isD-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl; 9= Xaa iscis,endo-octahydroindole-2-carbonyl” 17 Xaa Arg Pro Xaa Gly Xaa Ser XaaXaa Arg 1 5 10

We claim:
 1. A method for the treatment or prevention of the progress ofAlzheimer's disease comprising the step of administering to a host inrecognized need of such treatment an amount of a bradykinin antagonist,or a physiologically tolerable salt thereof, effective to achieve saidtreatment.
 2. The method as claimed in claim 1 wherein said bradykininantagonist is a peptide, or a physiologically tolerable salt thereof. 3.The method as claimed in claim 2 wherein said bradykinin antagonist is apeptide of the formula (I): Z—P—A—B—C—E—F—K—(D)Q—G—M—F′—I  (I) in whichZ is a₁) hydrogen, (C₁-C₈)-alkyl, (C₁-C₈)-alkanoyl,(C₁-C₈)-alkoxycarbonyl, (C₃-C₈)-cycloalkyl, (C₄-C₉)-cycloalkanoyl, or(C₁-C₈)-alkylsulfonyl, (1) in which 1, 2 or 3 hydrogen atoms in each of(C₁-C₈)-alkyl, (C₁-C₈)-alkanoyl, (C₁-C₈)-alkoxycarbonyl,(C₃-C₈)-cycloalkyl, (C₄-C₉)-cycloalkanoyl or (C₁-C₈)-alkylsulfonyl areoptionally replaced by 1, 2 or 3 identical or different radicalsselected from carboxyl, (C₁-C₄)-alkyl, (C₁-C₈)-alkylamino,(C₆-C₁₀)-aryl-(C₁-C₄)-alkylamino, hydroxyl, (C₁-C₄)-alkoxy, halogen,Di-(C₁-C₈)-alkylamino, Di-{(C₆-C₁₀)-aryl-(C₁-C₄)}-alkylamino, carbamoyl,phthalimido, 1,8-naphthalimido, sulfamoyl, (C₁-C₄)-alkoxycarbonyl,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₅)-alkyl, NHR(1), {(C₁-C₄)-alkyl}NR(1)or {(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl}NR(1), where R(1) is hydrogen or aurethane protective group, or (2) 1 or 2 hydrogen atoms in each of(C₁-C₈)-alkyl, (C₁-C₈)-alkanoyl, (C₁-C₈)-alkoxycarbonyl,(C₃-C₈)-cycloalkyl, (C₄-C₉)-cycloalkanoyl or (C₁-C₈)-alkylsulfonyl arereplaced by 1 or 2 identical or different radicals selected fromcarboxyl, amino, (C₁-C₈)-alkylamino, hydroxyl, (C₁-C₄)-alkoxy, halogen,di-(C₁-C₈)-alkylamino, carbamoyl, sulfamoyl, (C₁-C₄)-alkoxycarbonyl,(C₆-C₁₄)-aryl and (C₆-C₁₄)-aryl-(C₁-C₅)-alkyl, and 1 hydrogen atom ineach of (C₁-C₈)-alkyl, (C₁-C₈)-alkanoyl, (C₁-C₈)-alkoxycarbonyl,(C₃-C₈)-cycloalkyl, (C₄-C₉)-cycloalkanoyl, or (C₁-C₈)-alkylsulfonyl isoptionally replaced by a radical selected from (C₃-C₈)-cycloalkyl,(C₁-C₆)-alkylsulfonyl, (C₁-C₆)-alkylsulfinyl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkylsulfonyl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkylsulfinyl, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryloxy,(C₃-C₁₃)-heteroaryl and (C₃-C₁₃)-heteroaryloxy, a₂) (C₆-C₁₄)-aryl,(C₇-C₁₅)-aroyl, (C₆-C₁₄)-arylsulfonyl, (C₃-C₁₃)-heteroaryl, or(C₃-C₁₃)-heteroaroyl, or a₃) carbamoyl which can optionally besubstituted on the nitrogen by (C₁-C₈)-alkyl, (C₆-C₁₄)-aryl or(C₆-C₁₄)-aryl-(C₁-C₅)-alkyl, where for the radicals defined under a₁),a₂) and a₃) the aryl, heteroaryl, aroyl, arylsulfonyl and heteroaroylgroups are optionally substituted by 1, 2, 3 or 4 radicals selected fromcarboxyl, amino, nitro, (C₁-C₈)-alkylamino, hydroxyl, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl, (C₇-C₁₅)-aroyl, halogen, cyano,di-(C₁-C₈)-alkylamino, carbamoyl, sulfamoyl and (C₁-C₆)-alkoxycarbonyl;P is a direct bond or a radical of the formula (II),—NR(2)—(U)—CO—  (II) in which R(2) is hydrogen, methyl or a urethaneprotective group, U is (C₃-C₈)-cycloalkylidene, (C₆-C₁₄)-arylidene,(C₃-C₁₃)-heteroarylidene, (C₆-C₁₄)-aryl-(C₁-C₆)-alkylidene, each ofwhich can optionally be substituted, or is {CHR(3)}_(n), where n is 1-8,and R(3) independently of one another is hydrogen, (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₄)-aryl or (C₃-C₁₃)-heteroaryl, which with theexception of the hydrogen are in each case optionally monosubstituted byamino, substituted amino, amidino, substituted amidino, hydroxyl,carboxyl, carbamoyl, guanidino, substituted guanidino, ureido,substituted ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl,4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl,phthalimido, 1,8-naphthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, or in which U is{CHR(3)}_(n), where n is 1-8, and R(2) and R(3) together with the atomscarrying these radicals form a mono-, bi- or tricyclic ring systemhaving 2 to 15 carbon atoms; A is defined as P; B is a basic amino acidin the L or D configuration, which can be substituted in the side chain;C is a compound of the formula (IIIa) or (IIIb) G′—G′—Gly  (IIIa)G′—NH—(CH₂)_(p)—CO  (IIIb) in which p is 2 to 8, and G′ independently ofone another is a radical of the formula (IV) —NR(4)—CHR(5)—CO—  (IV) inwhich R(4) and R(5) together with the atoms carrying these radicals forma heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbonatoms; E is the radical of a neutral, acidic or basic, aliphatic oralicyclic-aliphatic amino acid; F is the radical of a neutral, acidic orbasic, aliphatic or aromatic amino acid which can be substituted in theside chain, or a direct bond; K is the radical —NH—(CH₂)_(x)—CO— wherex=1-4 or a direct bond; (D)Q is D-Tic, D-Phe, D-Oic, D-Thi or D-Nal,each of which can optionally be substituted by halogen, methyl ormethoxy, or a radical of the formula (V) below

in which X is oxygen, sulfur or a direct bond, and R is hydrogen,(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₄)-aryl or(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, where the alicycle of formula (V) canoptionally be substituted by halogen, methyl or methoxy; G is defined asG′ above or is a direct bond; M is defined as F; F′ is defined as F, isa radical —NH—(CH₂)_(q)—, where q=2 to 8, or, if G is not a direct bond,is a direct bond; and I is —OH, —NH₂ or NHC₂H₅, wherein I is notdirectly bonded to D(Q); or a physiologically tolerable salt thereof. 4.The method as claimed in claim 3 in which said bradykinin antagonist isa peptide of the formula (I), wherein: Z is as defined above under a₁),a₂) or a₃); P is a bond or a radical of the formula (II)—NR(2)—(U)—CO—  (II) where U is CHR(3), R(3) is as in claim 2, and R(2)is H or CH₃, wherein R(2) and R(3) together with the atoms carryingthese radicals can form a mono-, bi- or tricyclic ring system having 2to 15 carbon atoms; and A is a direct bond; or a physiologicallytolerable salt thereof.
 5. The method as claimed in claim 3 in whichsaid bradykinin antagonist is a peptide of the formula (I), wherein: Zis as defined above under a₁), a₂) or a₃); P is a bond or a radical ofthe formula (II) —NR(2)—(U)—CO—  (II) where R(2) is H or CH₃, U isCHR(3) and R(3) independently of one another is hydrogen, (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₄)-aryl, (C₃-C₁₃)-heteroaryl, which with theexception of the hydrogen in each case are optionally monosubstituted byamino, substituted amino, hydroxyl, carboxyl, carbamoyl, guanidino,substituted guanidino, ureido, mercapto, methylmercapto, phenyl,4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl,4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, or in which R(2) and R(3)together with the atoms carrying these radicals form a mono-, bi- ortricyclic ring system having 2 to 15 carbon atoms; A is a bond; and (D)Qis D-Tic; or a physiologically tolerable salt thereof.
 6. The method asclaimed in claim 2 wherein said bradykinin antagonist is a peptide ofthe formula: H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140);para-guanidobenzoyl-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-HypE(transpropyl)-Oic-Arg-OH;H-D-Arg-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Cpg-Cpg-Arg-OH;H-D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;H-Arg(Tos)-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH;H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH;Fmoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;Fmoc-Aoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;Fmoc-ε-aminocaproyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;benzoyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;cyclohexylcarbonyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;Fmoc-Aeg(Fmoc)-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;Fmoc-Aeg(Fmoc)-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;indol-3-yl-acetyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH;dibenzylacetyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH; or aphysiologically tolerable salt thereof.
 7. The method as claimed inclaim 2 wherein said bradykinin antagonist is a peptide of the formula:H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140);para-guanidobenzoyl-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH; or aphysiologically tolerable salt thereof.
 8. The method as claimed inclaim 2 wherein said bradykinin antagonist isH-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140), or aphysiologically tolerable salt thereof.
 9. The method as claimed inclaim 3 wherein n is 1-6 when P is a radical of formula (II) and U informula (II) is {CHR(3)}_(n).
 10. The method as claimed in claim 3wherein said optional substituted amino of R(3) is —N(A′)—Z, in which A′independently of one another is Z, Z being defined as in claim 3 undera₁) or a₂).
 11. The method as claimed in claim 3 wherein said optionalsubstituted amidino of R(3) is —(NH)C—NH—Z, in which Z is defined as inclaim 3 under a₁) or a₂).
 12. The method as claimed in claim 3 whereinsaid optional substituted guanidino of R(3) is —N(A′)—C(N(A′))—NH—Z, inwhich A′ independently of one another is Z, Z being defined as in claim3 under a₁) or a₂).
 13. The method as claimed in claim 3 wherein saidoptional substituted ureido of R(3) is —C(O)—N(A′)—Z, in which A′independently of one another is Z, Z being defined as in claim 3 undera₁) or a₂).
 14. The method as claimed in claim 5 wherein said optionalsubstituted amino of R(3) is —N(A′)—Z, in which A′ independently of oneanother is Z, Z being defined as in claim 3 under a₁) or a₂).
 15. Themethod as claimed in claim 5 wherein said optional substituted guanidinoof R(3) is —N(A′)—C(N(A′))—NH—Z, in which A′ independently of oneanother is Z, Z being defined as in claim 3 under a₁) or a₂).